HK1136827A1 - Spirocyclic cyclohexane derivatives - Google Patents

Spirocyclic cyclohexane derivatives Download PDF

Info

Publication number
HK1136827A1
HK1136827A1 HK10103563.9A HK10103563A HK1136827A1 HK 1136827 A1 HK1136827 A1 HK 1136827A1 HK 10103563 A HK10103563 A HK 10103563A HK 1136827 A1 HK1136827 A1 HK 1136827A1
Authority
HK
Hong Kong
Prior art keywords
unsubstituted
polysubstituted
mono
alkyl
samples
Prior art date
Application number
HK10103563.9A
Other languages
German (de)
French (fr)
Chinese (zh)
Other versions
HK1136827B (en
Inventor
Stefan Schunk
Derek Saunders
Stephanie Harlfinger
Sonja Steufmehl
Original Assignee
Grunenthal Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=39531427&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=HK1136827(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Grunenthal Gmbh filed Critical Grunenthal Gmbh
Publication of HK1136827A1 publication Critical patent/HK1136827A1/en
Publication of HK1136827B publication Critical patent/HK1136827B/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Obesity (AREA)
  • Reproductive Health (AREA)
  • Rheumatology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Endocrinology (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)

Abstract

Spirocyclic cyclohexane compounds corresponding to formula I in which R1 and R2 form a pyrrolidine ring or an azetidine ring and which exhibit increased metabolic stability, a process for producing such spirocyclic cyclohexane compounds, pharmaceutical compositions containing such spirocyclic cyclohexane compounds, and the use of such spirocyclic cyclohexane compounds to treat or inhibit pain and/or other disorders.

Description

The present invention relates to spirocyclic cyclohexane derivatives, methods of their manufacture, medicinal products containing these compounds and the use of spirocyclic cyclohexane derivatives in the manufacture of medicinal products.
The heptadecapeptide nociceptin is an endogenous ligand of the opioid receptor-like receptor (ORL1) (Meunier et al., Nature 377, 1995, p. 532-535), which belongs to the opioid receptor family and is found in many regions of the brain and spinal cord and has a high affinity for the ORL1 receptor. The ORL1 receptor is homologous to the μ, κ and 5 opioid receptors and the amino acid sequence of the nociceptin peptide is very similar to that of the known opioid peptides. Activation of the receptor induced by nociceptin via the injection of Gi/o-proteins leads to a copulatory union of the A and A proteins (Meunier et al., Nature 372, 1995, p. 535).
The nociceptin peptide has been shown to exhibit pronociceptive and hyperalgesic activity in various animal models after intercerebroventicular application (Reinscheid et al., Science 270, 1995, pp. 792-794). These findings can be explained by inhibition of stress-induced analgesia (Mogil et al., Neuroscience 75, 1996, pp. 333-337). An anxiolytic activity of nociceptin has also been demonstrated in this context (Jenck et al., Proc.
On the other hand, an antinociceptive effect of nociceptin has also been demonstrated in various animal models, particularly after intrathecal application, where nociceptin is antinociceptive in various pain models, for example in the tail flick test in the mouse (King et al., Neurosci. Lett., 223, 1997, 113-116).
The ORL1 receptor is also involved in the regulation of other physiological and pathophysiological processes, including learning and memory formation (Manabe et al., Nature, 394, 1997, p. 577-581), hearing (Nishi et al., EMBO J., 16, 1997, p. 1858-1864) and many others. An overview article by Calo et al. (Br.J. Pharmacol., 129, 2000, 1261-1283), provides an overview of the indications or biological processes in which the ORL1 receptor plays a role or is likely to play a role. These include analgesia, stimulation and regulation of the absorption of dopamine, the influence of μ-aminotransferase on the administration of morphine, the treatment of neurotoxic effects such as blood disorders, the excretion of neurotransmitters, the use of anticoagulants (especially anticoagulants), the use of anticoagulants (antimicrobials), the reduction of blood pressure, and in particular the use of anticoagulants (antimicrobials), anticoagulants (antimicrobials), anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants,
The potential applications of compounds that bind to the ORL1 receptor and activate or inhibit it are therefore varied. In addition, however, opioid receptors such as the μ-receptor and the other subtypes of these opioid receptors, namely δ and κ, play a major role in pain management, and it is therefore advantageous if the compound also has an effect on these opioid receptors.
WO 2004043967 reveals spirocyclic cyclohexane derivatives which have a high affinity for the ORL1 receptor but also for the μ-opioid receptor.WO 2004043967 generically reveals compounds where R1 and R2 form a ring, but no example compounds with this structural element are revealed. It only reveals example compounds where R1 and R2 mean H or CH3 with at least one of the residues R1 and R2 meaning H. These compounds show an exceptionally high affinity for the μ-opioid or ORL1 receptor, as shown by the relevant data.
Spirocyclic cyclohexane derivatives with affinity for the μ-opioid or ORL1 receptor are also known from WO 2005066183, which also reveals generic compounds in which R1 and R2 form a ring.
SPIROcyclic cyclohexane derivatives are also known from WO 2006108565 and have a high affinity for the μ-oploid or ORL1 receptor, where R1 and R2 are either H or CH3, where R1 and R2 do not mean H at the same time, or R1 and R2 form a ring with -(CH2) 4 or -(CH2) 5.
Metabolic stability is a crucial property for the efficacy of a compound and therefore for the success of drug development.The compounds shown as example compounds in WO 2004043967 are broken down in the body, inter alia, by N-demethylation.These metabolites are in turn biologically active.
In the development of medicinal products, active metabolites need to be studied extensively, so it is advantageous to develop compounds that form fewer metabolites.
The purpose of the present invention was to provide medicinal products that have a high nociceptin/ORL1 receptor system activity and a higher metabolic stability than the compounds described in WO 2004043967.
Surprisingly, certain compounds, although generically described in WO 2004043967 but not revealed by sample compounds, have now been found to have higher metabolic stability than the sample compounds revealed,
The invention is therefore concerned with spirocyclic cyclohexane derivatives of general formula I, , in which R1 and R2 form a ring and stand for -CH2CH2CH2 R3 for C1-5 alkyl, whether saturated or unsaturated, branched or unbranched, simply or multiple substitution or unsubstituted; C3-8 cycloalkyl, whether saturated or unsaturated, simply or multiple substitution or unsubstituted; aryl or heteroaryl, either unsubstituted or simply or multiple substitution, aryl bound to C1-3 alkyl group or C3-8 cycloalkyl, either unsubstituted or simply or multiple substitution; R5 for =O; H; C1-5 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or simply or repeatedly substituted: COOR13, CONR13, OR13; C3-8 cycloalkyl, saturated or unsaturated, unsubstituted or simply or repeatedly substituted; aryl,or heteroaryl, unsubstituted or simply or repeatedly substituted; or aryl, C3-8-cycloalkyl or heteroaryl, C1-3-alkyl bound, unsubstituted or simply or repeatedly substituted; R6 for H; F, Cl, NO2, CF3, OR13, SR13, SO2R13, SO2OR13, CN, COOR13, NR14R15; C1-5 alkyl, unsaturated or unsaturated, branched or unbranched, unsubstituted or simply or repeatedly substituted; C3-8 cycloalkyl, unsaturated or unsaturated, unsubstituted or simply or repeatedly substituted; aryl or heteroaryl, unsubstituted or simply or repeatedly substituted; or C1-3 alkyl, C3-8 cycloalkyl or heteroaryl, unsubstituted or simply or repeatedly substituted; or R5 and R6 together (CH2) n with n = 2, 3, 4, 5 or 6, wherein individual hydrogen atoms are also denoted by F,Cl, Br, I, NO2, CF3, OR13, CN or C1-5 alkyl may be substituted; R7, R8, R9 and R10 independently of each other for H, F, Cl, Br, I, NO2, CF3, OR13, SR13, SO2R13, NHC(=O)NR14R15, SO2NR14R15, SO2OR13 CN, COOR13, NR14R15; C1-5 alkyl, C3-8 cycloalkyl, unsubstituted or simply or repeatedly substituted; aryl, or heteroaryl, unsubstituted or simply or repeatedly substituted; or aryl, C3-8 cycloalkyl or heteroaryl, unsubstituted or simply or repeatedly substituted, bound to C1-3 alkyl, or aryl, C3-8 cycloalkyl or repeatedly substituted, or R13H; C1-5 alkyl, whether or not saturated or unsaturated, branched or unbranched, unsubstituted or simply or repeatedly substituted; C3-8 cycloalkyl, whether or not saturated or unsaturated, unsubstituted or simply or repeatedly substituted; aryl or heteroaryl, unsubstituted or simply or repeatedly substituted; or aryl bound by C1-3 alkyl,'C3-8 cycloalkyl' or 'heteroaryl' means unsubstituted or simply or repeatedly substituted; R14 and R15 independently H; C1-5 alkyl, whether or not saturated or unsaturated, branched or unbranched, unsubstituted or simply or repeatedly substituted; or C3-8 cycloalkyl, whether or not saturated or unsaturated, unsubstituted or simply or repeatedly substituted; aryl or heteroaryl, unsubstituted or simply or repeatedly substituted; or aryl bound by C1-3 alkyl, C3-8 cycloalkyl or heteroaryl, unsubstituted or simply or repeatedly substituted; or R14 and R15 together form CH2CH2OCH2CH2, CH2CH2NR16CH2CH2 or (CH2) 3-6, where R16H means C1-5 alkyl saturated or unsaturated, branched or unbranched, unsubstituted or simply or repeatedly substituted; X is O, S, SO, SO2 or NR17; R17 for H; C1-5 alkyl,Saturated or unsaturated, branched or not; COR12 or SO2R12, R12H; C1-5 alkyl, whether or not saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; C3-8 cycloalkyl, whether or not saturated or unsaturated, simply or repeatedly substituted or unsubstituted; aryl or heteroaryl, whether or not simply or repeatedly substituted or unsubstituted; or C1-3 alkyl-bound aryl, C3-8 cycloalkyl or heteroaryl, whether or not simply or repeatedly substituted or unsubstituted; OR13; NR14R15 means in the form of racemate; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers or a single enantiomer or diastereomer; the bases and/or salts of physiologically compatible acids or cations.
When summing different residues, e.g. R7, R8, R9 and R10, and summing residues on their substituents, e.g. OR13, SR13, SO2R13 or COOR13, a substituent, e.g. R13, may have different meanings for two or more residues, e.g. R7, R8, R9 and R10, within a substance.
The compounds of the invention show good binding to the ORL1 receptor and the μ-opioid receptor.
Err1:Expecting ',' delimiter: line 1 column 57 (char 56)
Err1:Expecting ',' delimiter: line 1 column 56 (char 55)
The term (CH2) 3-6 is understood to mean -CH2-CH2-CH2, -CH2-CH2-CH2, -CH2-CH2-CH2-CH2 and CH2-CH2-CH2-CH2.
Err1:Expecting ',' delimiter: line 1 column 56 (char 55)
Err1:Expecting ',' delimiter: line 1 column 56 (char 55)
Err1:Expecting ',' delimiter: line 1 column 103 (char 102)
Err1:Expecting ',' delimiter: line 1 column 63 (char 62)For example, two or three substitutions are made, for example, three times on the same C atom as in the case of CF3 or -CH2CF3 or at different places as in the case of -CH(OH) -CH=CH-CHCl2. The multiple substitution may be with the same or with different substituents. Ggf. a substituent may also be substituted; thus, O-Alkyl includes, but is not limited to, -O-CH2-CH2-O-CH2-CH2-OH. Preferably, for the purpose of this invention, an alkyl or cycloalkyl is substituted with F, Br, CN, Cl, I, CH3, C2H5, NH2, SH, NO3, OC3, OC2H5 or NCH2.
Err1:Expecting ',' delimiter: line 1 column 56 (char 55)
The term salt means any form of the active substance of the invention in which it takes or is charged in an ionic form and is coupled with or in solution with a antigene (a cation or anion). It also includes complexes of the active substance with other molecules and ions, in particular complexes complexed by ionic interactions. In particular, it includes (and this is also a preferred embodiment of the invention) physiologically compatible salts, in particular salts that are physiologically compatible with cations or bases and physiologically similar to anions or acids or also with a physiologically compatible acid or a physiologically compatible salt formed by a chemical reaction.
For the purposes of this invention, the term physiologically compatible salt with anions or acids means salts of at least one of the compounds of the invention - usually protonated, for example, to nitrogen - as a cation with at least one anion that is physiologically compatible, particularly when used in humans and/or mammals. In particular, for the purposes of this invention, it means the salt formed with a physiologically compatible acid, namely salts of the respective active substance with inorganic or organic acids that are physiologically compatible, especially when used in humans and/or mammals. Examples of physiologically compatible salts of certain acids are: aspartic acid, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acids, 2-amino acyl, 2-amino acyl, 2-amino acetyl, 2-amino acetyl, 2-amino acetyl, 2-amino acetyl, 2-amino acamino acamino acetyl, 2-amino acamino acamino acamino acamino acamino acamino acamino, 2-amino acamino acamino acamino acamino acamino acamino acamino, 2-amino acamino acamino acamino acamino acamino acamino acamino, 2-amino acamino acamino acamino acamino acamino acamino acamino, 2-amino acamino acamino acamino acamino acamino acamino acamino, 2-amino
For the purposes of this invention, the term salt formed from a physiologically compatible acid means salts of the active substance with inorganic or organic acids which are physiologically compatible, particularly when used in humans and/or mammals. Particularly preferred are hydrochloride and citrate. Examples of physiologically compatible acids are hydrochloric acid, hydrobromic acid, sulfuric acid, methanosulfonic acid, formic acid, acetic acid, oxalic acid, beryl stearic acid, tartaric acid, citric acid, fumaric acid, lactic acid, citric acid, glutamic acid, saccharomycin, monohydroxylic acid, 5-O-aminobenzene, 1-Hydroxybromoxylic acid, 4-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutylbutyl, 2-Hydroxybutylbutylbutylbutylbutyl, 2-Hydroxybutylbutylbutylbutyl, 2-Hydroxybutylbutylbutylbutyl, 2-Hydroxybutylbutylbutylbutyl, 2-Hydroxybutylbutylbutylbutyl, 2-Hydroxybutylbutylbutylbutyl and 2-Hydroxybutylbutylbutylbutylbutylbutyl and 2-Hydroxy.
For the purposes of this invention, the term physiologically compatible salt with cations or bases means salts of at least one of the compounds of the invention - usually a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation that is physiologically compatible, especially when used in humans and/or mammals.
For the purposes of this invention, the term salt formed with a physiologically compatible cation means salts containing at least one of the respective compounds as an anion with at least one inorganic cation which is physiologically viable, particularly when used in humans and/or mammals.
Err1:Expecting ',' delimiter: line 1 column 107 (char 106)
in the form of racemate; the enantiomer, diastereomer, mixture of enantiomers or diastereomers or a single enantiomer or diastereomer; the bases and/or salts of physiologically compatible acids or cations; preference is given to substituted cyclohexandrites of general formula I, in which: R3 for phenyl, benzyl or phenethyl, either unsubstituted or single or multiple substitutions on the ring; C1-5 alkyl, unsubstituted or single or multiple substitutions; C4-6 cycloalkyl, unsubstituted or single or multiple substitutions; Pyridyl, thienyl, thiazolyl, imidazolyl, 1,2,4 triazolyl or benzlmidazolyl, unsubstituted or single or multiple substitutions.
In particular, spirocyclic cyclohexane derivatives of general formula I, wherein R3 is phenyl, benzyl, phenethyl, thienyl, pyridyl, thiazolyl, imidazolyl, 1,2,4 triazolyl, benzimidazolyl or benzyl, unsubstituted or simply or repeatedly substituted with F, Cl, Br, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OC2H5 or NCH3) (2); ethyl, n-propyl, 2-propyl, allyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl or cyclopentyl, respectively, substituted or repeatedly substituted with OC2H5, OCH3 or simply, where thienyl, pyridyl, thlazolyl, imidazolyl, 1,2,4 triazolyl and benzimidazolyl are preferably unsubstituted; In particular: Phenyl, unsubstituted or simply substituted with F, Cl, CN, CH3; Thienyl; Ethyl, n-propyl or n-butyl, unsubstituted or simply or repeatedly substituted with OCH3, OH or OC2H5, in particular with OCH3. For a preferred embodiment of the spirocyclic cyclohexane derivatives of the invention, the following shall apply: the residue R5 for H, CH3, COOH, COOCH3, CH2OPhenyl, where the phenyl residue may be substituted with F, Cl, Br, I, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OC2H5 or N(CH3) 2 or CH2OH.
Particularly preferred are substituted cyclohexane derivatives, where R5 stands for H.
Preferably, substitution cyclohexanderivatives of the general formula I, where R6H may mean methyl, ethyl, CF3, benzyl or phenyl, where the benzyl or phenyl residue may be replaced by F, Cl, Br, I, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OC2H5 or N(CH3) 2.
Especially preferred are spirocyclic cyclohexane derivatives, where R6 stands for H.
Preferably, spirocyclic cyclohexane derivatives, where R7 R8, R9 and R10 are independently H; C1-5 alkyl, branched or unbranched, unsubstituted or single or multiple substituted; F, Cl, Br, I, CF3, OH, OCH3, NH2, COOH, COOCH3, NHCH3 Thienyl, pyrimidinyl, pyridinyl, NCH3) 2 or NO2 preferably R7 R8, R9 and R10 for H; C1-5 alkyl, branched or unbranched, unsubstituted or single or multiple substituted; F, Cl, Br, I, OH, OCH3, COOH, COOCH3, NH2, NHCH3 or N(CH3) 2 or NO2, whereas the remaining residues are H, or two of the residues R7 R8, R9 and R10 are independently of each other H; C1-5 alkyl, branched or unbranched, unsubstituted or single or multiple substituted, F, Cl, Br, I, OH, OCH3, COOH, COOCH3, NH2, NHCH3 or N(CH3) 2 or NO2, while the remaining residues are H.
Particular preference is given to spirocyclic cyclohexane derivatives, where R7 stands for R8, R9 and R10 independently of each other for H, F, OH, Cl or OCH3.
Compounds with X for O are particularly favoured, and compounds of general formula I, X for NR17, are particularly favoured.
The most preferred compounds are: 4- ((Azetidin-1-yl) - 4- ((3-fluorphenyl) - 2', 3', 4', 9'-tetrahydrospiro[cyclohexan-1,1'-pyrido[3,4-b]indol] (polar diastereomers) 4- ((Azetidin-1-yl) - 4- ((3-fluorphenyl) - 2-', 3', 4', 4', 9'-tetrahydrospiro[cyclohexan-1,1'-pyrido[3,4-b]indol] (Unpolar diastereomers) 4- ((Azetidin-1-yl) - 4- ((3-fluorphenyl) - 4-), 9'-dihydro-3'-H-spiro[cyclohexan-1,1'-pyrano[3,4-b]indol]One of the two possible diastereomers is 1- (((Azetidin-1-yl) - 4-fluorhexan-1-hydroxypropano-1,3-hydroxypropano-1,3-dihydroxypropano-1,3-dihydroxypropano-1,3-dihydroxypropano-1,3-dihydroxypropano-1,3-dihydroxypropano-1,3-dihydroxypropano-1,3-dioxypropan-1-hydroxypropano-1,3-dioxypropan-1-hydroxy) - 2- (Propano-1,4-dioxyprano-1,3-dioxyprano-1,3-dioxyprano-2-propano-2-dioxy) - 1-) - 1- (Propano-2-dioxyprano-1,4-dioxyprano-1,3-dioxyprano-1,4-dioxyprano-1,3-dioxyprano-1,4-dioxyprano-2-dioxy) - 2-) - 2- (Propano-2-dioxyprano-1,4-dioxyprano-1,4-dioxyprano-1,4-dioxyprano-1,3-dioxyprano-1,4-dioxyprano-2-dioxy) - 2-) - 2-) - 2- (Propano-1,4-dioxyprano-1,4-dioxyprano-1,4-dioxyprano-1,4-dioxyprano-1,4-dioxyprano-1,4-dioxyprano-2-dioxyprano-2-dioxy) - 2-) - 2- (Propano-2-dioxy) - where appropriate, as a mixture.
The substances of the invention, for example, act on the ORL1 receptor relevant for various diseases, making them suitable as pharmaceutical active substances in a medicinal product.
The compounds of the invention have a similar affinity for the μ-opioid or ORL1 receptor as the compounds shown as sample compounds in WO 2004043967, but are more metabolically stable than these compounds and are therefore particularly suitable for drug development.
The medicinal products of the invention contain, in addition to at least one spirocyclic cyclohexane derivative of the invention, suitable additives and/or excipients, as appropriate, as well as carrier materials, fillers, solvents, diluents, dyes and/or binders, and may be administered as liquid forms in the form of solutions for injection, drops or juices, as semi-solid forms in the form of granules, tablets, pellets, patches, capsules, pills/spray sprays or aerosols. The specific characteristics of the excipients, as well as the degree of recycling of the granules, depend on whether the product is sprayed, whether or not it is intended for oral administration, or for intra-venous administration. The medicinal products of the invention, known as Cyclohexan, can be administered in the form of tablets, tablets, pellets, patches, capsules, or other preparations, such as intra-cutaneous or intra-ocular injections, or in the form of oral or intramuscular injections.
The dose to be administered to the patient will vary according to the patient' s weight, type of application, indication and severity of the disease, usually 0.00005 to 50 mg/kg, preferably 0.001 to 0.5 mg/kg, of at least one spirocyclic cyclohexane derivative of the invention.
For all the above forms of medicinal products, it is particularly preferable that the product contains, in addition to at least one spirocyclic cyclohexane derivative, another active substance, in particular an opioid, preferably a strong opioid, in particular morphine, or an anaesthetic, preferably hexobarbital or halothane.
A spirocyclic cyclohexane derivative of the invention is present in a preferred form of the medicinal product as a pure diastereomer and/ or enantiomer.
As can be seen in the introduction to the state of the art, the ORL1 receptor has been identified in pain in particular, and therefore spirocyclic cyclohexane derivatives of the invention can be used to manufacture a medicinal product for the treatment of pain, in particular acute, neuropathic or chronic pain.
Therefore, another subject matter of the invention is the use of a spirocyclic cyclohexane derivative of the invention to manufacture a medicinal product for the treatment of pain, in particular acute, visceral, neuropathic or chronic pain.
Another subject matter of the invention is the use of a spirocyclic cyclohexane derivative of the invention to manufacture a medicinal product for the treatment of anxiety, stress and stress-related syndromes, depression, epilepsy, Alzheimer's disease, dementia, general cognitive dysfunction, learning and memory disorders (as a nootropic), disorders, alcohol and/ or drug and/ or drug abuse and/ or dependence, sexual dysfunction, cardiovascular disease, hypotension, hypertension, tincture, pruritus, migraine, difficulty hearing, insufficient bowel movements, anti-inflammatory drug use, analgesic analgesics, anti-retroviral drugs, diuretics, diuretics, to treat mood disorders or neurological disorders, and/or to treat narcolepsy, narcolepsy, and/or narcolepsy, and/or to treat narcolepsy with a drug or other drug, or to treat narcolepsy, narcolepsy, and/or narcolepsy, or to reduce the sensitivity to narcotic drugs, or to reduce the sensitivity to narcotic drugs, or to reduce the sensitivity to narcotic drugs, or to reduce the sensitivity to narcotic drugs, or to reduce the sensitivity to narcotic drugs, or to reduce the sensitivity to narcotic drugs, or to narcotic drugs.
It may be preferred in one of the above uses if a spirocyclic cyclohexane derivative is used as a pure diastereomer and/or enantiomer, as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and/or enantiomers.
The invention also relates to a procedure for the treatment, in particular in one of the above indications, of a non-human mammal or human being requiring the treatment of pain, in particular chronic pain, by the administration of a therapeutically active dose of a spirocyclic cyclohexane derivative of the invention or of a medicinal product of the invention.
Another subject of the invention is a process for the production of the spirocyclic cyclohexane derivatives of the invention as described and illustrated below, in particular a process for the production of a spirocyclic cyclohexane derivative of the invention by translating a cyclohexane underivative of the general formula E into an inderivative of the general formula F or H. Other
Tryptopholes of type F (Y = O) can be reacted in reactions of the Oxa-Pictet Spengler type and tryptamines of type H in reactions of the Pictet Spengler type with ketones, with the addition of at least one suitable reagent from the group of acids, acid anhydrides, esters or weakly acidic reactive salts or leucic acids, to form products of formula I. For X = SH, the reaction is analogous.
Preferably, at least one reagent from the group of carbonic, phosphoric or sulphonic acids or their respective anhydrides, carbonic triethylsyl esters, acidic salts, mineral acids or leucic acids selected from the group consisting of boron trifluoride, indium ((III) chloride, titanium tetrachloride, aluminium ((III) chloride, or with the addition of at least one transition metal salt, preferably with the addition of at least one transition metal triflate (transition metal triethyl methacrylate sulphonate), in particular preferably with the addition of at least one transition metal triethyl methacrylate of the group containing Scandium (III) trifluoride, obtained from indium (III) or triethyl methacrylate, or, if appropriate, from an aromatic or non-aromatic solvent, such as acetone or triethyl methacrylate, or, in the case of solvents, from acetone or triethyl methacrylate, or from an aqueous solution, or from a solvent, or, if appropriate, from an aqueous solution, in aqueous solution, or, or, in aqueous solution, or, or, in the presence of a solution, or in solution, or in solution, or in solution, with acetone or, or, or, in the presence of a solution, of triethyl methacrylate or, or, or, or, in the presence of any other solvent;
In particular, preference is given to pyridinium para-toluol sulphonate, phosphorus pentoxide in the presence of celite, boron trifluoride etherate, trifluoric acid, orthotitan tetrazine propyl ester together with trifluoric acid, trifluoromethan sulphonic acid urethrimethyl silyl ester, trifluoromethan sulphonic acid, methan sulphonic acid, trifluoric acid, acetic acid, phosphoric acid, polyphosphoric acid, polyphosphate ester, p-toluol sulphonic acid, hydrochloric acid HCl gas, sulphuric acid together with acpu, tin tetrachloride. Other
Secondary amines of type Ib can be acylated, sulphonylated or carbamoylated to L/M/N compounds by known techniques, preferably at elevated temperatures, preferably under microwave irradiation.
Such a method, known to the professional, may be the implementation with an anhydride or an acid chloride with the addition of a base, e.g. triethylamine.
Synthesis of ketone building blocks
Compounds of formula E can be released from corresponding acetals C or their salts D by means of acid clearance methods known to the expert, X being selected from the group of alkyl, alkyl/alkylide/ with aryl or alkyl (saturated/unsaturated) substituted alkylide Other
Amino acetals C with two substituents on the nitrogen atom can also be obtained by adding carbon nucleophiles to salts of enamines Qa, preferably with known methods. Organometallic compounds in inert solvents
The production of imines is known from the literature. Other
Generally, acetals C can also be obtained by substitution of suitable starting groups Z in structures of formula B.
The starting groups are preferably cyanogroups; 1,2,3-triazole-1-yl groups; other suitable starting groups are 1H-benzo[d][1,2,3]triazole-1-yl groups and pyrazol-1-yl groups (Katritzky et al., Synthesis 1989, 66-69).
A particularly preferred route to compounds of structure C is the conversion of aminonitryl B with corresponding organometallic compounds, preferably Grignard compounds, preferably in ethers, preferably in RT. The organometallic compounds are either available commercially or can be produced by known methods.
Another particularly preferred route to compounds of structure C is the conversion of aminotriazols B with corresponding organometallic compounds, preferably Grignard compounds, preferably in ethers, preferably in RT. The organometallic compounds are either available on the market or can be produced by methods known in the literature. Other
Structures of formula B can be produced by reaction of ketones A with amines and acid reactants Z-H. Suitable reactants Z-H are e.g. hydrogen cyanide, 1,2,3-triazole, benzotriazole or pyrazol.
A particularly preferred route to compounds of structure B is the conversion of ketones with metal cyanides and the corresponding amine in the presence of acid, preferably in an alcohol, at temperatures of - 40 to 60 °C, preferably at room temperature with alkali metal cyanides in methanol.
Another particularly preferred route to compounds of structure B is the transposition of ketones with 1,2,3-triazole and the corresponding amine in the presence of water-repellent conditions, preferably using a water separator at elevated temperature in an inert solvent or using molesieb or another drying agent.
The following citations are particularly relevant: Jirkovsky et al., J. Heterocycl. Chem., 12, 1975, 937-940; Lett et al., J. Chem. Soc. Perkin 1, 1992, 813-822; Shinada et al., Tetrahedron Lett., 39, 1996, 7099-7102; Garden et al., Tetrahedron, 58, 2002, 8399-8412; Lednicer et al., J. Med., 23, 1980, 424-430; Chemini et al., J. Org. Chem., 67, 15; 5386-5389; Davis et al., J. Med., 31, 31, 27, 27, 27, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29,
Examples
The following examples are intended to explain the invention in more detail but do not limit the general idea of the invention.
The yields of the compounds produced are not optimized.
All temperatures are uncorrected.
Err1:Expecting ',' delimiter: line 1 column 54 (char 53)
The stationary phase for column chromatography was silica gel 60 (0.040 - 0.063 mm) from E. Merck, Darmstadt.
The thin-film chromatographic studies were carried out with HPTLC-prepared plates, silica gel 60 F 254, by E. Merck, Darmstadt.
The mixing ratios of the reagents used for chromatographic examinations are always given in terms of volume.
The following substances are to be classified in the same category as the product:
The following shall be added to the list of active substances:
A mixture of 4 N hydrochloric acid (8.1 ml), methanol (4.9 ml) and azetidine (8.5 g, 10 ml, 149 mmol) was first given 1,4-dioxaspirone[4.5]decan-8-on (4.84 g, 31 mmol) and then potassium cyanide (4.85 g, 74.4 mmol) in water (15 ml) under ice-cooling. The mixture was stirred at room temperature for 5 days, then added to water (50 ml) and extracted with diethyl ether (3 × 50 ml). The combined organic phases were dried with sodium sulphate and pressed in i.v.
Production: 6.77 g (98%) and oil
The mean value of the measurements of the test chemical is calculated as follows:
The following information is provided for the purpose of the analysis:
A 2 M solution of phenylmagnesium chloride in tetrahydrofuran (12 ml, 24 mmol) was dripped with a solution of 8-azetidin-1-yl-1,4-dioxaspiro[4,5]decan-8-carbonitrile (2,20 g, 9,9 mmol) in anhydrous tetrahydrofuran (25 ml) under argon and ice cooling and stirred overnight at room temperature. After addition of saturated ammonium chloride solution (5 ml) and water (5 ml), the phases were separated and the aqueous was extracted with diethyl ether (3 × 50 ml). The organic phases were dried with sodium sulphate and vacuum sewn. The product was cleaned by flash chromatography (100 g, 20 × 4.0 cm) with cyclohexane (1:1) ethanol.
The following is the list of products which are to be classified in the same heading as the product:
The mean value of the measurements of the test chemical is calculated as follows:
Stage 3: 4-Azetidine-1-yl-4-phenylcyclohexanone (ketoblock 1)
A solution of 1- ((8-phenyl-1,4-dioxaspiro[4,5]dec-8-yl) acetidine (370 mg, 1.3 mmol) in acetone (30 ml) was mixed with 6 N hydrochloric acid (2 ml) and stirred overnight at room temperature.
The yield is 274 mg (92%) white solid
Melting point: not determined
The mean value of the measurements of the test chemical is calculated as follows:
The following shall be added to the list of active substances:
The following shall be added to the list of active substances:
A mixture of 4N hydrochloric acid (17 ml) and methanol (10 ml) was added under ice-cooling to contain pyrrolidine (22.5 ml, 0.306 mol), cyclohexane-1,4-dione-monoethylene ketal (10.0 g, 0.064 mol) and potassium cyanide (10.0 g, 0.15 mol). The mixture was stirred at room temperature for 74 h and then extracted after addition of water (80 ml) with diethyl ether (4 × 70 ml). The residue was then absorbed in dichloromethane (70 ml) and dried with magnesium sulphate overnight. The organic phase was frozen and the 8-pyrrolidine-1-dioxyl-1,4-canaspirone[4,5]dehydroxydeethyl-8-carbon was obtained as a white solid with a melting point of 65-67 °C (10.7 g) in a white solution (10.68%).
The following shall be added to the list of active substances:
To prepare the reaction mixture, a 1,82 M solution of phenylmagnesium chloride in THF (70 ml, 0,127 mol) was added to a saturated ammonium chloride solution (100 ml) under freezing and then re-hydrated with diethyl ketyl (3 × 100 ml) under argon and ice cooling for 15 min. The organic phase was mixed with water (70 ml) and saturated NaCl (70 ml) and then mixed with water (0,0 ml) and ice. The product was then dissolved into a liquid crystal (10,8 ml), except for the 4-hydroxyethyl methacrylate (8,8 ml), which was dissolved in a white solid of 4-hydroxyethyl methacrylate (8,3 ml) with a residual of ethyl methacrylate (8,3 ml).
Stage 3: 4-pyrrolidine-4-yl-4-phenylcyclohexanone (ketoblock 2) is used
The hydrochloride 4-(8-Phenyl-1,4-dioxaspiro[4,5]dec-8-yl) pyrrolidine hydrochloride (5,8 g, 17,9 mmol) was dissolved in 7,5 N hydrochloric acid (16 ml) and stirred at room temperature for 24 h. After completion of hydrolysis, the reaction mixture was extracted with diethyl ether (2 × 50 ml), the aqueous phase was made alkaline by 5 N sodium chloride ice cooling, extracted with dichloromethane (3 × 50 ml) and eaten. The ketone 4-Pyrrolidine-4-yl-4-phenylcyclohexanone was isolated as a gel solid with a melting point of 75-79 °C and a yield of 96 % (4,1 g).
The following substances are to be classified in the same heading as the active substance:
The following shall be added to the list of active substances:
To a solution of 1,4 dioxaspiro[4,5]decan-8,on (3.9 g, 25 mmol) in toluene (40 ml), pyrrolidine (1.95 g, 2.29 ml, 27.5 mmol), 1,2,3-triazole (2.07 g, 30 mmol) and molybdenum 4 Å (7.14 g) were added, stirred at 90 °C for 7 h, then decanted and immediately recycled.
The following shall be reported in the table of the active substance:
The reaction mixture was stirred overnight at room temperature and then poured into saturated ammonium chloride solution (60 ml). The phases were separated and the aqueous phases were extracted with diethyl ether (3 × 70 ml). The combined organic phases were purified with sodium sulphate, i.e. vacuum, and the residue (12 g) by flash chromatography (400 g, 20 x 7,6 g) with ethyl acetate methanol (9:1) per cm.
yield: 2,70 g (40% over two stages), brown oil
The mean value of the dose of the active substance is calculated as the following:
Stage 3: 4-butyl-4-pyrrolidine-1-yl-cyclohexanone (ketoblock 3) is used
A solution of 1-(8-Butyl-1,4-dioxaspiro[4,5]dec-8-yl) pyrrolidine (2.70 g, 10.1 mmol) in acetone (100 ml) was mixed with water (10.0 ml) and 37% hydrochloric acid (14.0 ml) and stirred overnight at room temperature. The mixture was then slowly dripped with 4 M sodium salts until pH 10 was reached. The mixture was extracted with diethyl ether (4 × 40 ml), the combined organic phases were dried with sodium sulphate and i.i. vacuum cleaned. The raw product (2.6 g) was cleaned by flash chromatography (260 g, 30 × 5.6 cm) with ethyl acetate / methanol (9:1).
Production: 1.06 g (47%) of brown oil
The mean value of the measurements performed was calculated as follows: 1H-NMR (DMSO-d6): 0.88 (t, 3H, J = 6.7 Hz); 1.14-1.34 (m, 4H); 1.40-1.50 (m, 2H); 1.62-1.88 (m, 8H); 2.04 (dt, 2H, J = 15.0, 3.9 Hz); 2.42 (ddd, 2H, J = 6.3, 11.8, 15.5 Hz); 2.63 (t, 4H, J = 6.0 Hz).
The following substances are to be classified in the same category as the active substance:
The following shall be added to the list of active substances:
A solution of 1,4-Dioxaspiro[4,5]decan-8-on (4,69 g, 30 mmol) and 4-Methoxybenzylamine (5,35 g, 5,06 ml, 39 mmol) in anhydrous tetrahydrofuran (45 ml) was mixed with 4 Å (6 g) of molibdenum and stirred at room temperature for 20 h. For analytical purposes, an aliquot portion of the solution was removed and compressed i.v.
The mean value of the 1H-NMR (CDC/3) is 1.76-1.87 (m, 2H); 1.91 (t, 2H, J = 6.4 Hz); 2.53 (t, 4H, J = 6.5 Hz); 3.79 (s, 3H); 4.00 (s, 4H); 4.49 (s, 2H); 6.85 (d, 2H, J = 7.9 Hz); 7.21 (d, 2H, J = 8.1 Hz).
The sample contains 4-methoxybenzylamine. The reaction mixture was filtered and the reaction solution was used in the next step without further processing.
The following substances are to be classified in the same category as the active substance:
In a heated flask, a 2 M solution of benzylmagnesium chloride in tetrahydrofuran (10 ml, 20 mmol) was slowly dripped in a heated flask with a 0.6 M solution of (1,4-dioxaspiro[4,5]dec-8-ylide) -(4-methoxybenzyl) amine in tetrahydrofuran (17 ml, 10 mmol) under argon and ice cooling. The mixture was stirred at room temperature for 20 h and then dripped to 20 % ammonium chloride solution (20 ml) under ice water cooling. The organic phase was separated and the water was extracted with diethyl ether (3 × 20 ml). The combined organic phases were compressed with 2 nuts (20 ml) and water (20 ml) and washed with e-cyclamethylamine. The product was then washed with a liquid of 75% (170 × 22 cm) and treated with a liquid of 75% (17% × 22%) ethanol (170 × 22 cm) by means of a vacuum cleaner.
Production: 1.27 g (34%) yellowish oil
The first proton was not identified, but the second proton was not identified, and the second proton was not identified.
The following substances are to be classified in the additive:
6 M saline acid (7 ml) was added to a solution of (8-benzyl-1,4-dioxaspiro [4,5 ]dec-8-yl) ((4-methoxybenzyl) amine (1.2 g, 3.3 mmol) in acetone (17 ml). The reaction solution was stirred at room temperature for 20 h, then made basic (pH-9) with 25% potassium carbonate solution and extracted with diethyl ether (3 × 20 ml). The combined organic phases were dried with sodium sulphate and compressed to approximately 10 ml in the i.v. The precipitate was filtered out and dried in the i.v.
The yield is 790 mg (74%), white solid
The melting point is 122-124 °C
The mean value of the measurements of the test chemical is calculated as the following:
The following substances are to be classified in the additive:
The following shall be added to the list of active substances:
A 1 M solution of 3-fluorphenylmagnesium bromide in tetrahydrofuran (250 ml, 250 mmol) was dripped with a solution of 8-azetidine-1-yl-1,4-dioxaspiro[4,5]decan-8-carbonitrile (13.9 g, 62.53 mmol) in anhydrous tetrahydrofuran (13.9 g, 62.53 mmol) under argon and ice cooling and stirred at room temperature for 24 h. Then saturated ammonium chloride solution (150 ml) was added under ice cooling and stirred vigorously for 20 min. The rich phases were then separated and the wet phase (3 x 50 ml) extracted with diethyl ether. The dried organic phases were purified with sodium tri sulfate and pressed. The product was obtained in a vacuum obtained from a solution of 18 (99%) sodium sulfate in crude oil.
The substance is classified as a substance of very high concern in the Union for the purposes of the definition of the product.
The raw product (18 g, 61.8 mmol) was dissolved in ethyl methyl ketone (100 ml), put under ice cooling with ClSiMe3 (30 ml, 0.237 mol) and stirred in an open flask at room temperature.
Stage 3: 4- (acetidine-1-yl) 4- (fluorophenyl) cyclohexanone (ketoblock 5)
A solution of the hydrochloride (20 g, 61 mmol) obtained in water (50 ml) was mixed with concentrated hydrochloric acid (50 ml) and acetone (50 ml) and stirred at room temperature for 48 h. The pH was adjusted by adding 5 N of sodium salts and then the aqueous phase was extracted with dichloromethane (3 x 100 ml). The combined organic phases were dried with sodium sulphate and vacuum-insulated. The raw product (15 g) was purified by column chromatography [silicon gel 60 (150 g); ethyl acetate (1000 ml) ], thus obtaining the desired ketone at a yield of 6 (40%) %.
The following substances are to be classified in the additive:
The following information shall be provided in the form of a summary of the results of the analysis:
After 10 minutes, this reaction mixture was mixed with a solution of 2-bromathiophen (5.7 g) in 10 ml THF. After starting the Grignard reaction, 2-bromathiophen (15 ml) dissolved in 50 ml THF was added by drip and after the addition was completed stirred for two hours at room temperature.
This reaction mixture was treated with 8-Azetidine-1-yl-1,4-dioxaspiro[4,5]decan-8-carbonitrile (12 g) dissolved in 60 ml THF, dripped at 60-70 °C at nitrogen atmosphere, stirred at room temperature for 1 hour and the reaction progress was monitored by thin film chromatography (50% EtOAc/hexane).
After complete turnover, the reaction mixture was cooled to 0 °C, agitated with saturated ammonium chloride solution (50 ml) and finally extracted with ethyl acetate (2x 100 ml). The combined organic phases were dried with Na2SO4. After removal of the solvent under reduced pressure, the residue was column chromatographically cleaned (silica, 5-10% EtOAc/hexane). The resulting product was obtained as a brown solid (10,2 g, 68%).
The following information is provided for the purpose of the analysis:
The reaction was controlled by thin-film chromatography (75% EtOAc/hexane). After complete turnover, the methanol was distilled, the residue was returned with water (150 ml) and extracted with ethylac (2x100 ml). The combined organic phases were dried using Na2SO4. After removal of the solvent, the residue was brought to cold water (150 ml) under reduced pressure, the solution was filtered for 1 hour and then reduced to a solid. The product was obtained in the form of a dilute solution of ethylac (SO6.5 and 784%) and dried after removal.
Example A-1
N-{6'-Fluor-4',9'-Dihydro-4-Phenyl-spiro[cyclohexane-1,1'(3'H) -Pyrano[3,4-b]indol]-4-yl}-azetidin, 2-hydroxy-1,2,3-propantricarboxylate (2:1) (One of two possible diastereomers)
A solution of 4-azetidine-1-yl-4-phenylcyclohexanone (ketobactone 1) (270 mg, 1.18 mmol) and 5-fluorotriptophol (211 mg, 1.18 mmol) in anhydrous dichloromethane (30 ml) was mixed at 5-10 °C with trifluoromethanesulphonic acid (235 mg, 138 μl, 1.57 mmol) and stirred at room temperature overnight. After adding 0.5 M sodium salts (10 ml), the phases were separated and the aqueous phases were extracted with dichloromethane (3 × 10 ml). The combined organic phases were dried with sodium sulphate and vacuum-sealed. The raw product (280 mg) was flash-chromatographed (18 mg, 20 × 2.0 cm) with triethylamethylamine cycloacetate (1:1) and purified.
The yield is 119 mg (29%), white solid The melting point is 249-257 °C
The mean value of the measurements performed was calculated as follows: 1.63 to 1.78 (m, 6H); 2.12 (d, 2H, J = 12.6 Hz); 2.23 to 2.35 (m, 2H); 2.63 (t, 2H, J = 5.4 Hz); 2.97 (t, 4H, J = 6.7 Hz); 3.85 (t, 2H, J = 5.3 Hz); 6.86 (dt, 1H, J = 9.4, 2.6 Hz); 7.13 (dd, 1H, J = 10.1, 2.5 Hz); 7.26 to 7.45 (m, 6H); 11.01 (s, 1H).
The mean value of the sampling intervals for the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples of samples of the samples of samples of the samples of samples of the samples of samples of samples of the samples of samples of samples of samples of the samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samples of samp
A solution of freshly obtained spiroeters (119 mg, 0.3 mmol) in hot isopropanol (60 ml) was added to isopropanol (5 ml) with citric acid (72 mg, 0.37 mmol).
The yield is 120 mg (82%) white solid The melting point is 189 to 194 °C.
The mean value of the measurements of the test chemical is given by the following formulae:
The total number of doses administered to each patient was calculated by dividing the total dose by the total dose of the drug administered to each patient.
The following table shows the data for the calculation of the reference value: N-{6'-Fluor-4',9'-Dihydro-4-phenyl-spiro[cyclohexane-1,1'(3'H) -pyrano[3,4-b]indol]-4-yl}-pyrrolidine, 2-hydroxy-1,2,3-propantricarboxylate (2:1) (One of two possible diastereomers)
A solution of 4-pyrrolidine-4-yl-4-phenylcyclohexaneone (ketobactone 2) (486 mg, 2 mmol) and 5-fluorotriptophol (358 mg, 2 mmol) in anhydrous dichloromethane (20 ml) was mixed with trifluoromethanesulfonic acid (399 mg, 232 μl, 2.66 mmol) at 5-10 °C and stirred overnight at room temperature.
The first group:
The yield is 390 mg (48%) white solid The following shall be added to the list of active substances:
The mean value of the measurements performed was calculated using the following formulae: 1.60-1.90 (m, 10H); 2.23 (t, 3H, J = 13.1 Hz); 2.39 (d, 3H, J = 12.9 Hz); 2.64 (t, 2H, J = 5.3 Hz); 3.89 (t, 2H, J = 5.3 Hz); 6.88 (dt, 1H.
The mean value of the sampling intervals for the samples of the active substance (s) shall be calculated from the sampling intervals for the samples of the active substance (s) and the sampling intervals for the samples of the active substance (s).
The second group:
yield: 140 mg (17%) white solid The melting point is 188-191 °C
The mean value of the measurements of the test chemical is given by the following equations: 1.59 (br s, 4H); 1.76-1.88 (m, 1H); 2.08-2.20 (m, 2H); 2.34-2.48 (m, 3H); 2.52-2.60 (m, 2H); 2.66 (d, 1H, J = 18.5 Hz); 2.80 (t, 3H, J = 7.3 Hz); 3.47 (dd, 2H, J = 13.1, 7.3 Hz); 4.58 (t, 1H, J = 5.3 Hz); 6.22 (s, 1H); 6.77-6.84 (m, 1H); 6.81 (dt, 1H, J = 8.8, 1.9 Hz); 7.12-7.24 (m, 3H); 7.32 (t, 2H, J = 7.6 Hz); 7.48 (d, 2H, J = 7.9 Hz); 10.07 (s, 1H).
The mean value of the sampling intervals for the samples of the active substance (s) and the sampling intervals for the samples of the active substance (s) and the sampling intervals for the samples of the active substance (s) and the sampling intervals for the samples of the active substance (s) and the sampling intervals for the samples of the active substance (s) and the sampling intervals for the samples of the active substance (s) and the sampling intervals for the samples of the active substance (s) and the sampling intervals for the samples of the active substance (s) and the sampling intervals for the samples of the active substance (s) and the sampling intervals for the samples of the active substance (s) and the sampling intervals for the samples of the active substance (s) and the sampling intervals for the samples of the active substance (s) and the sampling intervals for the samples of the active substance (s) and the sampling intervals for the samples of the samples of the active substance (s) and the sampling intervals for the samples of the samples of the samples of the active substance (s) and the samples for the samples of the samples of the samples of the samples of the samples of the samples of the active substance (s) and the samples of the samples of the samples of the samples of the samples of the samples of the samples of the samples were samples taken.
Fraction 1 and fraction 2 are identical compounds.
A solution of the newly obtained fraction 1 (230 mg, 0.57 mmol) in boiling isopropanol (180 ml) was mixed with citric acid (138 mg, 0.71 mmol) in hot isopropanol (10 ml), producing a thick white precipitate A-2 within a few seconds, which was filtered after cooling.
The following table shows the results of the analysis: The melting point is 263 to 270 °C.
The mean value of the measurements performed was 1.65 (br s, 4H); 1.76 (d, 2H; J = 12.5 Hz); 1.88 (t, 2H, J = 13.6 Hz); 2.24 (t, 2H, J = 12.4 Hz); 2.43 (d, 2H, J = 12.9 Hz); 2.52-2.68 (m, 8H); 2.72 (d, 2H, J = 15.3 Hz); 3.88 (t, 2H, J = 5.4 Hz); 6.88 (dt, 1H, J = 9.4, 2.6 Hz); 7.14 (dd, 1H, J = 9.94, 2.47 Hz); 7.22-7.30 (m, 1H); 7.31-7.46 (m, 5H); 10.79 (s, 1H).
The total number of doses administered to each patient was calculated by dividing the total doses by the total number of doses administered to each patient.
The following is a list of the types of vehicles which are subject to the requirements of this Regulation: N-{4',9'-Dihydro-4-phenyl-spiro[cyclohexane-1,1'(3'H) -pyrano[3,4-b]indol]-4-yl}-pyrrolidine, 2-hydroxy-1,2,3-propantricarboxylate (4:3) (Unpolar diastereomer) with a purity by weight of more than 0,5%
The ketobacteria block 2 (4-pyrrolidine-4-yl-4-phenylcyclohexanone) (243 mg, 1 mmol) was presented together with tryptopholic acid (161 mg, 1 mmol) in absolute dichloromethane (50 ml). The solution was then mixed with methanosulfonic acid (0.13 ml, 2 mmol). The solution was stirred at room temperature for 16 h without precipitation. The reaction mixture was mixed with 1N NaOH (20 ml) and stirred for one hour. The organic phase was separated and the aqueous phase was extracted with dichloromethane (2 × 20 ml). The organic phases were combined, compressed and dried to obtain the desired spiroxene as a diastereoisomer (30 mg, 78%).
The resulting spiroether diastereoisomer (303 mg, 0.78 mmol) was agitated with methanol (60 ml) for 15 min, the residue separated by filtration (248 mg) and decrystallized from 2-propanol (150 ml).
The resulting pure unpolar spiroether (89 mg, 0.23 mmol) was mixed with ethanol (45 ml) and heated to 60 °C. To this suspension, citric acid was added in ethanol (48 mg, 0.25 mmol, 5 ml) and stirred for 10 min at 60 °C and 1 h at room temperature. The unpolar cltrat A-3 was extracted and isolated as a colourless solid (75 mg, 17%) with a melting point of 259 °C.
The following is a list of the types of vehicles which are to be used: N-{4',9'-Dihydro-4-phenyl-spiro[cyclohexane-1,1'(3'H) -pyrano[3,4-b]indol]-4-yl}-pyrrolidine, 2-hydroxy-1,2,3-propantricarboxylate (1:1, polar diastereomer) with a purity by weight of not more than 0,5%
The spiroether diastereoisomer mixture (103 mg, 0.285 mmol) retained in example A-3 was dissolved in ethanol (80 ml) at 60 °C and heated with citric acid in ethanol (54 mg, 0.28 mmol, 5 ml). It was stirred for 1 h at room temperature and the initially precipitated unpolar citrate (85 mg, 19%) was separated by filtration. The filtrate was compressed to 2 ml, precipitated with diethyl ether (40 ml) and the precipitated colourless solid was sifted. The polar citrate A-4 was obtained at a 16 % (73 mg) melting point of 179-180 °C.
The following is a list of the types of vehicles which are to be used: N-{6'-Fluor-4,9'-Dihydro-4-Butyl-spiro[cyclohexane-1,1'(3'H) -Pyrano[3,4-b]indol]-4-yl}-pyrrolidine, 2-hydroxy-1,2,3-propantricarboxylate (1:1) (One of two possible diastereomers)
A solution of 4-butyl-4-pyrrolidine-1-yl-cyclohexaneone (ketobactone 3) (1.06 g, 4.7 mmol) and 2- ((5-fluor-1H-3-yl) ethanol (854 mg, 4.7 mmol) in anhydrous dichloromethane (60 ml) was refrigerated and stirred with trifluoromethane sulphonic acid (949 mg, 552 μl, 6.3 mmol) in argon for one day at room temperature, followed by further addition of trifluoromethane sulphonic acid (300 mg, 174 μl, 2 mmol) and stirred again at room temperature for one day. The reaction mixture was then stirred with 0,5 mL of water (48 mg) and stirred for 20 min. The separated phase was mixed with 20 × 20 g of chloromethane (280 × 20 ml) and mixed with the extracted raw organic methanol (1,5 g/ml) and mixed with the extracted methanol (1,5 g/ml) and mixed with the extracted organic methanol (1,5 g/ml) and mixed with the extracted organic methanol (1,5 g/ml) for 20 min.
The yield is 370 mg (19%) of yellow solid (fraction 1) The product was present as a hydrochloride, the hydrochlorocarbon probably derived from the chloroform used for chromatography.
The mean value of the drug (CDC/ 3) was 0.97 (t, 3H, J = 6.8 Hz), 1.35-1.41 (m, 4H); 1.46-1.52 (m, 2H); 1.57 (d, 2H, J = 14.6 Hz), 1.89-1.98 (m, 4H); 2.22 (dt, 2H, J = 14.6, 6.0 Hz), 2.35-2.45 (m, 2H); 2.72 (t, 2H, J = 5.3 Hz), 2.78 (dt, 2H, J = 14.6, 3.5 Hz); 3.10 (dt, 2H, J = 13.0, 6.9), 3.63 (dt, 2H, J = 12.2 and 6.6 Hz), 3.92 (t, 2H, J = 5.3 Hz), 6.81 (dt, 1H, J = 9.2 and 1.06), 2.5 (dt, 1H = 9.7, Jdd), 7.07 (dt, 2H, J = 9.7 Hz), 2.4 (dt, 2H, J = 10.8 Hz), 4.5 (dt, Jdd), 10.04 (dt, Jdd), 1 (dt, 4.5 Hz); 1 (dt, Jdd), 10.04 (dt, Jdd), and 1 (dt, 1.06 (dt, 1.06), 1.36 (dt, Jdd), 1.04 (dt, Jdd, 1.04 (dt, 1.06), 1.06 (dt, 1.06), 1.06 (dt, 1.06 (dt, Jdd), 1.06 (dt, 1.06), 1.06 (dt, 1.06 (dt, 1.06), 1.06 (dt, 1.06), 1.06 (dt, 1.06 (dt, 1.8); 1.06 (Jdd), 1.08 (Jdd), 1.
The mean value of the measurements performed was calculated using the following formulae:
In addition, contaminated product (fraction 2.322 mg, 17%) and unrecycled ketone (fraction 3.227 mg, 23%) were obtained.
The 1H-NMR spectrum of the raw product mixture showed that only one diastereoisomer and the alkene had been formed, the latter not being isolated.
A solution of fraction 1 (350 mg, 0.83 mmol) in chloroform (20 ml) was washed with sodium hydrogen carbonate solution, the organic phase was dried with sodium sulphate and the solution was compressed into an i.v.
The following is the list of active substances in the feed additive: The melting point is 70 °C.
The mean value of the measurements of the test chemical is calculated by multiplying the mean value of the measurements by the mean value of the measurements of the test chemical by the mean value of the measurements of the measurements of the test chemical by the mean value of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measurements of the measur
The total number of cells in the sample was approximately equal to the total number of cells in the sample, i.e. approximately 10 g/m2 (i.e. approximately 10 g/m2).
A solution of the newly obtained yellow solid (free base of fraction 1) (180 mg, 0.46 mmol) in hot ethanol (15 ml) was added to a hot solution of citric acid (90 mg, 0.46 mmol) in ethanol (1.2 ml), resulting in a white precipitate which was filtered after cooling.
The yield is 137 mg (50%) white solid (A-5)
The mean value of the measurements performed was based on the following data: pH-NMR (DMSO-d6): 0.92 (t, 3H, J = 6.7 Hz); 1.20-1.40 (m, 4H); 1.44-1.64 (m, 4H); 1.71 (br d, 2H, J = 12.7 Hz); 1.90 (br s, 6H); 2.12 (br t, 2H, J = 12.7 Hz); 2.57 (d, 2H, J = 15.0 Hz); 2.63 (t, 2H, J = 4 Hz); 2.66 (d, 2H, J = 15.0 Hz); 3.07 (br s, 4H); 3.89 (t, 2H, J = 5.1 Hz); 6.87 (dt, 1H, J = 9.1, 2.4 Hz); 7.15 (dd, 1H, J = 9.9, 2.3 Hz); 7.37 (dd, 1H, J = 8.5, 4.4 Hz); 10.64 (s), 1H; 11H = 2-12 (approximately 2-3 hours).
The following is a reference comparison example RV-6: N-{6'-Fluor-4',9'-Dihydro-4-Benzyl-spiro[cyclohexane-1,1'(3'H) -Pyrano[3,4-b]indol]-4-yl}-amine
Stage 1: 4-benzyl-6'-fluor-N- ((4-methoxybenzyl) -4,9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indol]-4-amine (One of two possible diastereomers)
The reaction mixture was stirred at room temperature for another 20 h. The mixture was then stirred with 0.5 ml of sodium salts (24 ml) and then stirred at room temperature 2. The organic phase was separated and the dry phase was extracted with dihydromethane (3 ml). The organic phase was mixed with sodium chloride (50 ml) and washed with sodium vanadium.
yield: 1,07 g (94%), white solid The melting point is 76-79 °C.
The mean value of the test chemical is calculated by dividing the mean value of the test chemical by the mean value of the test chemical (see paragraphs 4.1, 5.2, 5.3, 5.4, 5.8, 5.8, 5.8, 5.8, 5.9, 125, 125, 125, 125, 125, 125, 125, 125, 125, 125, 125, 125, 125, 125, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, 135, and so on the other two samples, the following samples are the following samples
A solution of citric acid (96 mg, 0.5 mmol) in ethanol (0.5 ml) was added to a hot solution of the newly prepared spiroether (120 mg, 0.25 mmol) in ethanol (1 ml). After cooling, the solution was added to diethyl ether (20 ml). The precipitation was filtered, washed with ethanol and diethyl ether and dried in a vacuum.
The yield is 70 mg (41%) white solid The melting point is 135 °C to 141 °C.
The mean value of the measurements performed was calculated as follows: 1H-NMR (DMSO-d6): 1.53-1.84 (m, 6H); 1.95-2.15 (m, 2H); 2.62 (q, 4H, J = 15.3 Hz); 2.55-2.65 (m, 2H); 2.88 (s, 2H); 3.77 (s, 3H); 3.81 (t, 2H, J = 5.3 Hz), 3.97 (s, 2H); 6.86 (dt, 1H, J = 9.3, 2.5 Hz); 6.98 (d, 2H, J = 8.5 Hz); 7.20-7.37 (m, 7H); 7.48 (d, 2H, J = 8.5 Hz); 10.66 (s, 1H).
The following is added to the list of active substances:
A solution of the free base of 6'-fluor-4',9'-dihydro-N-(4-methoxybenzyl) -benzyl-spiro[cyclohexane-1,1'(3'H) -pyrano[3,4-b]indol]-4-amine citrate (200 mg, 0,4 mmol) in tetrahydrofuran (20 ml) and methanol (20 ml) was treated with 10 per cent palladium on activated carbon (40 mg) and hydrated for 7 h at 3 bar and 40 °C. The reaction mixture was then filtered by a crease filter, the filter residue washed with methanol and the filtrate was compressed in a vacuum. The raw product (186 cm) was cleaned by flash chromatography (20 g × 21 mg) with methanol.
The results of the analysis were published in the European Pharmacopoeia, the European Pharmacopoeia and the European Pharmacopoeia, and the European Pharmacopoeia, the European Pharmacopoeia and the European Pharmacopoeia.
The total number of samples of the active substance is calculated by dividing the total number of samples of the active substance by the total number of samples of the active substance.
Example A-7 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C4.]
The ketobacteria 5 (742 mg, 3 mmol) and tryptamine (481 mg, 3 mmol) were dissolved in MeOH (30 ml). The clear yellow reaction solution was stirred at room temperature for 16 h. The MeOH was then removed at the rotary evaporator and the residue was dissolved in 1,2-dichlorethane (30 ml). After adding trifluoroacetic acid (3 ml, 40 mmol), the solution was stirred at room temperature for 3 h. The rate of the reaction was controlled by DC. For processing, the solution was placed under ice-cooled with 5 N NaOH (50 ml). The aqueous phase was separated and extra-atomically combined with dichlorethane (3 × 30 ml). The organic phase was further diluted with NaOH2 (200 ml) and then separated into a white solid (20 ml) by a diisocyanate (20 mg) (20 ml) (20 ml) (20 ml) (20 ml) of diisocyanate (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) of diisocyanate (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20 ml) (20) (20) (20 ml) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20) (20)
The polarized product (A-7) was obtained at a yield of 355 mg (30%) at a melting point of 186-188 °C.
The maximum residue concentration of the active substance is calculated as the sum of the concentrations of the active substances in the active substance and the concentrations of the active substances in the active substance.
The more nonpolar product was obtained at a yield of 110 mg (9%) and a melting point of 277 to 281 °C.
The following are the most commonly used methods for the determination of the concentration of a substance in food:
Example A-8 The following shall be reported for the product:
Example A-8 is the nonpolar diastereomer obtained in example A-7.
Example A-9 4- (acetidine-1-yl) -4- (fluorphenyl) -4,9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-blindol] (One of two possible diastereomers)
The ketobacteria 5 (495 mg; 2 mmol) and tryptopholes (322 mg; 2 mmol) were dissolved in dry dichloromethane (20 ml). At 0 °C, trifluoromethanesulfonic acid trimethylsilyl ester (465 μl, 2.4 mmol) was added. The red-brown suspension was stirred at room temperature for 16 h. The course of the reaction was monitored by thin film chromatography. For processing, the approach was put under ice cooling with 5N NaOH (50 ml). The aqueous phase was separated and extracted with diethyl chloride (3 × 30 ml). The combined organic phases were dried over Na2SO4 and then dried to a tight consistency. Two white solids (20 ml) were removed from the mother diethyl ester, which contained no more spirox.
A-9 was obtained at a yield of 240 mg (31%) at a melting point of 270-274 °C.
The mean value of the measurement of the effects of the test chemical on the human body is calculated by dividing the mean value of the measurement of the effects of the test chemical by the mean value of the measurement of the effects of the test chemical on the human body.
Example A-10
It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]
Cinnamic acid chloride (371 mg, 2.23 mmol) was dissolved in abs tetrahydrofuran (30 ml) under argon and transferred to the free base of the more polar spiroamine A-7 (290 mg, 0.744 mmol) dissolved in abs tetrahydrofuran (15 ml) at room temperature for 20 min. After a reaction time of 1.5 h, the cloudy solution was diluted with water (10 ml), ice cooled with 1 N of baking soda (10 ml) and stirred for 2 h. Tetrahydrofuran was removed in a vacuum. A solid was released, separated by filtration and washed with water (3 × 5 ml). A raw product (350 mg) was isolated, which was chromatographed [60 mg]; 60 g of amylase (50 ml) was obtained from polar amylase (50 mg) in a solution of 120-926 mg of A to 120 °C.
The following table shows the data for the calculation of the average of the values of the two samples of the samples:
Example A-11
4- (Azetidine-1-yl)-6'-fluor-4- (Thiophen-2-yl)-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indol] 2-hydroxypropan-1,2,3-tricarboxylate (1:1) (Diastereomer) which is not polar
The ketone block 6 (706 mg, 3 mmol) was presented with 5-fluorotriptophol (537 mg, 3 mmol) in dichloromethane (50 ml) and then added to the solution by icing with trifluoromethanosulfonic trimethyl silyl ester (0.64 ml, 3.3 mmol) dissolved in dichloromethane (2 ml). The solution was stirred at room temperature for 24 h. The reaction mixture was stirred with water (10 ml) and 2N NaOH (10 ml) for 20 min. The further treatment of the reaction mixture involved the organic separation and the aqueous phase of the solution with hydrated ethyl chloride (0.64 ml, 3.3 mmol). The organic extract was obtained from the oil with a concentration of 20 g/ml (2,2 g/l) of polar ethanol (1,660 mg/l) and obtained after a purification process in a clearer than clear water solution (< 0.4 g/l) of distilled diesel (1,660 mg/l).
To produce the citrate, the unpolar spiroether (160 mg, 0.4 mmol) was dissolved in hot isopropanol (40 ml) and mixed with an equally hot isopropanol citric acid solution (80 mg, 0.4 mmol in 3 ml). The reaction mixture was then stored in the refrigerator for 16 hours. The resulting solid was sucked away. The desired citrate was obtained as a white solid (melting point 174-176 °C) at a yield of 193 mg (78%)
The total number of samples of the active substance shall be calculated by dividing the total number of samples of the active substance by the total number of samples of the active substance.
Studies on the efficacy of compounds of the invention: Measurement of ORL1 binding
The cyclohexane derivatives of generic formula 1 were tested in a receptor binding assay with 13H-nociceptin/orphanine FQ on membranes of recombinant CHO-ORL1 cells, using the test system presented by Ardati et al. (Mol. Pharmacol., 51, 1997, p. 816-824), where the 3H-nociceptin/orphanine FQ concentration was 0.5 nM. The binding acid was obtained with 20 μg of membrane protein per 200 μl of ED in 50 mM of heps, pH 7.4, 10 mM MgCl2 and 1 mMTA. The binding to the ORL1 receptor was determined by 1 mg of Wadssham-S (Pharma-Pyridine, Kiiburg, Kiiburg), measured in the table of the free-floating inhibition of SGAA, and is expressed as 1 μg of the inhibition in the inhibition of c-Methyl-Alyl-methyl-Alyl-Alyl-Alyl-Alyl-Alyl-Aly-Alyc-Alyc-Aly-Aly-Aly-ly-A-ly-ly-A-ly-ly-A-ly-A-ly-ly-A-ly-ly-A-ly-ly-A-ly-A-ly-A-ly-ly-A-ly-ly-A-ly-ly-A-ly-A-ly-ly-A-ly-A-ly-A-ly-ly-A-ly-A-ly-ly-A-ly-A-ly-ly-A-ly-A-ly-A-ly-ly-A-ly-A-ly-A-ly-A-ly-A-ly-A-ly-A-ly-A-ly-A-ly-A-ly-A-ly-A-ly-A-ly-A-ly-A-A-ly-ly-A-A-ly-A-ly-A-ly-A-ly-A-A-ly-ly-A-A-ly-A-ly-A-A-ly-ly-A-A-ly-A-A-ly-A-
Measurement of the μ-binding
The receptor affinity for the human μ-opioid receptor was determined in a homogeneous microtiter plate approach by dilution series of the substituted spirocyclic cyclohexane derivative to be tested with a receptor membrane preparation (15-40 μg protein per 250 μl incubation approach) of CHO-K1 cells expressing the human μ-opioid receptor (RB-HOM receptor membrane preparation from NEN, Zaventem, Belgium) in the presence of 1 nmol/l of the radioactive ligand [3H] naloxone (NET719, NENEN, Zaventem, Belgium) and 1 mg WPA-SPA (WPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPAThe percentage of displacement of the radioactive ligand from its binding to the human μ-opioid receptor was determined at a concentration of the test substance of 1 μmol/l and reported as the percentage inhibition (% inhibition) of the specific binding. The percentages were calculated from the displacement by varying concentrations of the compound at different concentrations to a general inhibition of the radioactive ligand at a concentration of 50 per cent of the IC 0650 inhibiting the inhibition of the radioactive ligand.The conversion using the Cheng-Prusoff relation yielded Ki values for the test substances.
In some cases, the determination of the Ki value was omitted and only inhibition was determined at a test concentration of 1 μM.
The Commission also noted that the Commission had not received any comments from interested parties.
Comparisons were made between compounds with the same base group and only differing in R1 and R2 residues. Due to the high affinity of dimethyl or monomethyl compounds from WO 2004043967 to the μ-opioid receptor and the ORL1 receptor, affinities are given as Ki values or as % inhibition at a test concentration of 1 μM. This test concentration is particularly low and is suitable for detecting particularly affinity compounds. R3 = phenyl, R8 = F, R5, R6, R7, R9, R10 = H, X = O
V-1 99 0.0032 86 0.0027
V-2 91 0.0112 100 0.0008
V-3 0 17 0.7367
V-4 2 8
V-5 76 65 1.4100
A-1 91 0.0123 101 0.0019
RV-2 56 0.3833 98 0.0018
V-6 18 39
V-7 -8 2.9000 -16 6.9433
The two compounds V-1 and V-2 have a very high affinity for the μ-opioid and the ORL1 receptor. In the case of the μ-opioid receptor, the Ki value is in the low nanomolar range, in the case of the ORL1 receptor in the single-digit low two-digit nanomolar range. The replacement of a CH3 group by a phenyl or benzyl residue results in compounds that only have an affinity in the micromolar range (V-6, V-7). In the case of ring closures between the R1 and R2 residues to the piperidin, morpholin or piperazin ring, the affinity is not lost, however, at values in the micromolar range.
As shown in the table above, the N-demethyl metabolite of V-1, V-2, has similar activity to parent substance V-1. Since an active metabolite must undergo extensive drug development studies, avoiding a metabolite is advantageous. A-1 and RV-2 do not form the N-demethyl metabolite. Conversion rates of A-1 and RV-2 have been shown to be low compared to V-1 liver microsomes. Surprisingly, A-1 and RV-2 show particularly low conversion rates on human liver microsomes compared to mouse liver microsomes. R3 = phenyl, R5, R3, R7, R8, R9, R10 = H, X = O Other
V-8 98 0.0002 96 0.0012
V-9 5 -3
RV-3 95 0.0035 84 0.0011
RV-4 61 0.11 100 0.0098
V-10 -2 43
V-11 -12 2
Only the compound RV-3, where NR1R2 stands for pyrrolidine, has a V-8-like affinity for μ and ORL1 receptors respectively. R3 = n-butyl, R8 = F, R5, R6, R7, R9, R10 = H, X = O Other
V-12 0.0016 µM 0.0009 µM
V-13 6 39
RV-5 47 94
V-14 9 42
V-15 8 34
In the series mentioned in 3.), only compound A-5 has a very high affinity for the μ-opioid receptor, in addition to compound V-12 (NR1R2 = dimethylamine). R3 = benzyl, R3 = F, R5, R6, R7, R9, R10 = H, X = O Other
RV-6 27 90
V-16 1 11 38
V-17 5 39
V-18 10 26
V-19 8 -2
V-20 -3 7
V-21 49 1,2 µM
The comparison series shown in (4) shows that R1 and R2 = H also lead to very active compounds compared to various other substitution possibilities.
Very good affinities for μ and ORL1 receptors were also found for the following examples: Other
A-8 0,0008 0,0009
A-9 0.0048 0,0020
A-11 0,0066 0,0048
Comparative studies on metabolic stability
The metabolic stability of the sample compound A-1 and the reference comparator compound RV-2 was compared with the stability of the compound V-1.
For this purpose, the substances were incubated in vitro with liver microsomes (mouse, human) and their metabolic stability was compared.
The method:
For the microsome incubations, stock solutions of A-1), RV-2 and V-1 were added to 10 mmol/l DMSO and diluted with incubation buffer to 10 μmol/l. 4% BSA (bovine serumalbumin) was added to the incubation buffer (100 mmol/l potassium phosphate, pH 7.4) to improve the stability of the substances in solution and to prevent nonspecific losses due to adsorption effects. The microsomes (mouse and human) were only diluted shortly before the experiment and diluted with incubation buffer to 3 nmol/ml P450 The co-factor solution (10 mmol/l NADP, 10 mmol/l glutamate-6-phosphate) was added at 37°C and 5 mmol/l incubator.
The incubation approaches were 250 μl: 150 μl incubation buffer + 25 μl 10 μmol/l substrate solution + 25 μl Mlkrosome dilution (3 nmol P450/mL), the enzymatic reaction was initiated by adding 50 μl co-factor solution. The incubation times were 0.5.10 and 15 min. at 37°C. The reactions were stopped by adding 50 μl acetonitrile.
In addition to the substances to be examined, Verepamll was incubated as a positive control to ensure the metabolic activity of the microsomes used.
The organic phase was steamed under nitrogen and incorporated into 400 μl of 50% acetonitrile/tetrahydrofuran (v:1) v (v) 50% water with 0.1% formic acid.
The substances were quantified by a sensitive and specific LC-MS/MS method, calibration samples (0.1-1 μmol/L) were added to each analyte in an incubation buffer + 4% bovine serum albumin and extracted from the incubation samples.
The result:
The metabolic turnover rate of RV-2 with mouse microsomes is reduced by 22% compared to that of V-1; with human microsomes the turnover rate decreases to about 30% of that of V-1. Other
Substrat [1 µmol/l] Umsatzrate humane Mikrosomen (300 pmol/ml) [nmol/min/nmol P450] Umsatzrate Mikrosomen der Maus (300 pmol/ml) [nmol/min/nmol P450]
V1 0.0300 0.0255
RV2 0.0105 0.0200
A1 kein Umsatz feststellbar 0.0009
The conclusion:
The rate of NADP-dependent microsomal biotransformation is reduced in the compounds of the invention relative to a methylated amino group. The extent of this reduction is specific and is more pronounced in human microsomes than in mouse microsomes.
Parenteral solution of a spirocyclic cyclohexane derivative
38 g of one of the spirocyclic cyclohexane derivatives, here reference comparator RV-3, is dissolved in 1 I water for injection at room temperature and then adjusted to isotonic conditions by addition of anhydrous glucose for injection.

Claims (16)

  1. Spirocyclic cyclohexane derivatives having the general formula I, wherein R1 and R2 together form a ring and denote -CH2CH2CH2-R3 denotes C1-5 alkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C3-8 cycloalkyl, in each case saturated or unsaturated, mono- or polysubstituted or unsubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; aryl or C3-8 cycloalkyl bonded via a C1-3 alkyl group, in each case unsubstituted or mono- or polysubstituted; R5 denotes =O; H; C1-5 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; COOR13, CONR13, OR13; C3-8 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl or heteroaryl, unsubstituted or mono- or polysubstituted; or aryl, C3-8 cycloalkyl or heteroaryl bonded via C1-3 alkyl, unsubstituted or mono- or polysubstituted; R6 denotes H; F, Cl, NO2, CF3, OR13, SR13, SO2R13, SO2OR13, CN, COOR13, NR14R15; C1-5 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono-or polysubstituted; C3-8 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl or heteroaryl, unsubstituted or mono- or polysubstituted; or aryl, C3-8 cycloalkyl or heteroaryl bonded via C1-3 alkyl, unsubstituted or mono- or polysubstituted; or R5 and R6 together denote (CH2)n where n = 2, 3, 4, 5 or 6, wherein individual hydrogen atoms can also be replaced by F, Cl, Br, I, NO2, CF3, OR13, CN or C1-5 alkyl; R7, R8, R9 and R10 independently of one another denote H, F, Cl, Br, I, NO2, CF3, OR13, SR13, SO2R13, SO2OR13, NHC(=O)NR14R15, SO2NR14R15, CN, COOR13, NR14R15; C1-5 alkyl, C3-8 cycloalkyl, unsubstituted or mono-or polysubstituted; aryl or heteroaryl, unsubstituted or mono- or polysubstituted; or aryl, C3-8 cycloalkyl or heteroaryl bonded via C1-3 alkyl, unsubstituted or mono- or polysubstituted; wherein R13 denotes H; C1-5 alkyl, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C3-8 cycloalkyl, in each case saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl or heteroaryl, unsubstituted or mono- or polysubstituted; or aryl, C3-8 cycloalkyl or heteroaryl bonded via C1-3 alkyl, unsubstituted or mono- or polysubstituted; R14 and R15 independently of each other denote H; C1-5 alkyl, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; or C3-8 cycloalkyl, in each case saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl or heteroaryl, unsubstituted or mono- or polysubstituted; or aryl, C3-8 cycloalkyl or heteroaryl bonded via C1-3 alkyl, unsubstituted or mono- or polysubstituted; or R14 and R15 together form CH2CH2OCH2CH2, CH2CH2NR16CH2CH2 or (CH2)3-6, wherein R16 denotes H; C1-5 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; X denotes O, S, SO, SO2 or NR17; R17 denotes H; C1-5 alkyl, saturated or unsaturated, branched or unbranched; COR12 or SO2R12, wherein R12 denotes H; C1-5 alkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C3-8 cycloalkyl, in each case saturated or unsaturated, mono- or polysubstituted or unsubstituted; aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or aryl, C3-8 cycloalkyl or heteroaryl bonded via C1-3 alkyl, in each case mono- or polysubstituted or unsubstituted; OR13, NR14R15; in the form of the racemate; the enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a single enantiomer or diastereomer; the bases and/or salts of physiologically compatible acids or cations.
  2. Spirocyclic cyclohexane derivatives according to claim 1, wherein "alkyl substituted" or "cycloalkyl substituted" denotes alkyl or cycloalkyl substituted with F, Cl, Br, I, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OC2H5 or N(CH3)2 and "aryl substituted" or "heteroaryl substituted" denotes aryl or heteroaryl substituted with F, Cl, Br, I, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OC2H5 or N(CH3)2.
  3. Spirocyclic cyclohexane derivatives according to claim 1, wherein R3 denotes phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted at the ring; C1-5 alkyl, unsubstituted or mono- or polysubstituted; C4-6 cycloalkyl, unsubstituted or mono- or polysubstituted; pyridyl, thienyl, thiazolyl, imidazolyl, 1,2,4-triazolyl or benzimidazolyl, unsubstituted or mono- or polysubstituted.
  4. Spirocyclic cyclohexane derivatives according to claim 3, wherein R3 denotes phenyl, unsubstituted or monosubstituted with F, Cl, CN, CH3; thienyl; ethyl, n-propyl or n-butyl, unsubstituted or mono- or polysubstituted with OCH3, OH or OC2H5, in particular with OCH3.
  5. Spirocyclic cyclohexane derivatives according to claim 1, wherein the radical R5 denotes H, CH3, COOH, COOCH3, CH2O-phenyl, wherein the phenyl radical can be substituted with F, Cl, Br, I, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OC2H5 or N(CH3)2, or CH2OH.
  6. Spirocyclic cyclohexane derivatives according to claim 1, wherein R6 can denote H; methyl, ethyl, CF3, benzyl or phenyl, wherein the benzyl or phenyl radical can be substituted with F, Cl, Br, I, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OC2H5 or N(CH3)2.
  7. Spirocyclic cyclohexane derivatives according to claim 1, wherein R7, R8, R9 and R10 independently of one another denote H; C1-5 alkyl, branched or unbranched, unsubstituted or mono- or polysubstituted; F, Cl, Br, I, CF3, OH, OCH3, NH2, COOH, COOCH3, NHCH3, thienyl, pyrimidinyl, pyridyl, N(CH3)2 or NO2.
  8. Spirocyclic cyclohexane derivatives according to one of claims 1 to 7, wherein X denotes O.
  9. Spirocyclic cyclohexane derivatives according to one of claims 1 to 7, wherein X denotes NR17.
  10. Spirocyclic cyclohexane derivatives according to claim 1, from the group comprising N-{6'-Fluoro-4',9'-dihydro-4-phenylspiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-yl}-azetidine, 2-hydroxy-1,2,3-propanetricarboxylate (2:1) 4-(Azetidin-1-yl)-4-(3-fluorophenyl)-2',3',4',9'-tetrahydrospiro[cyclohexane-1,1'-pyrido[3,4-b]indole] (polar diastereomer) 4-(Azetidin-1-yl)-4-(3-fluorophenyl)-2',3',4',9'-tetrahydrospiro[cyclohexane-1,1'-pyrido[3,4-b]indole] (non-polar diastereomer) 4-(Azetidin-1-yl)-4-(3-fluorophenyl)-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole] (one of two possible diastereomers) 1-(4-(Azetidin-1-yl)-4-(3-fluorophenyl)-3',4'-dihydrospiro[cyclohexane-1,1'-pyrido[3,4-b]indol]-2'(9'H)-yl)-3-phenylprop-2-en-1-one (polar diastereomer) 4-(Azetidin-1-yl)-6'-fluoro-4-(thiophen-2-yl)-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole] 2-hydroxypropane-1,2,3-tricarboxylate (1:1) (non-polar diastereomer) optionally also as a mixture.
  11. Process for the preparation of spirocyclic cyclohexane derivatives according to claim 1, characterised in that a reactant having the general formula E is reacted with addition of acid or the trimethylsilyl esters thereof, for example trifluoromethanesulfonic acid trimethylsilyl ester, trifluoromethanesulfonic acid, acetic acid, phosphoric acid, methanesulfonic acid or trifluoroacetic acid, in a suitable solvent, for example dichloroethane, dichloromethane, chloroform, acetonitrile, diethyl ether or nitromethane, with a reactant having the general formula F or H, wherein the radicals R1 to R3 and R5 to R10 have the meanings given in claim 1.
  12. Process for the preparation of spirocyclic cyclohexane derivatives according to claim 1, wherein X denotes NR17 and R17 denotes COR12 or SO2R12, characterised in that a spirocyclic cyclohexane derivative in which X denotes NH is reacted with an anhydride or an acid chloride with addition of a base, for example triethylamine, preferably under microwave radiation.
  13. Process for the preparation of spirocyclic cyclohexane derivatives according to claim 1, wherein X denotes SO or SO2, characterised in that a spirocyclic cyclohexane derivative in which X denotes S is oxidised with the aid of an oxidising agent, for example H2O2.
  14. Medicament containing at least one spirocyclic cyclohexane derivative according to one of claims 1 to 10, optionally in the form of its racemate, the pure stereoisomers, in particular enantiomers and diastereomers, in any mixing ratio; in the form of its acids or its bases or in the form of its salts, in particular the physiologically compatible salts or salts of physiologically compatible acids or cations; or in the form of its solvates, in particular the hydrates, and optionally containing suitable additives and/or auxiliary substances and/or optionally further active ingredients.
  15. Use of a spirocyclic cyclohexane derivative according to one of claims 1 to 10, optionally in the form of its racemate, the pure stereoisomers, in particular enantiomers and diastereomers, in any mixing ratio; in the form of its acids or its bases or in the form of its salts, in particular the physiologically compatible salts or salts of physiologically compatible acids or cations; or in the form of its solvates, in particular the hydrates, for the preparation of a medicament for the treatment of pain, in particular acute, neuropathic or chronic pain.
  16. Use of a spirocyclic cyclohexane derivative according to one of claims 1 to 10 to prepare a medicament for the treatment of anxiety conditions, stress and stress-related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, learning and memory disorders (as a nootropic), withdrawal symptoms, alcohol and/or drug and/or prescription drug abuse and/or dependency, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinnitus, pruritus, migraine, hearing impairment, gastrointestinal motility disorders, food intake disorders, anorexia, obesity, locomotive disorders, diarrhoea, cachexia, urinary incontinence, or as a muscle relaxant, anticonvulsant or anaesthetic, or for coadministration in treatment with an opioid analgesic or with an anaesthetic, for diuresis or antinatriuresis, anxiolysis, for the modulation of motor activity, for the modulation of neurotransmitter release and treatment of associated neurodegenerative diseases, for the treatment of withdrawal symptoms and/or for the reduction of the addiction potential of opioids.
HK10103563.9A 2007-02-22 2008-02-19 Spirocyclic cyclohexane derivatives HK1136827B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102007009319.7 2007-02-22
DE102007009319A DE102007009319A1 (en) 2007-02-22 2007-02-22 Spirocyclic cyclohexane derivatives
PCT/EP2008/001271 WO2008101660A1 (en) 2007-02-22 2008-02-19 Spirocyclic cyclohexane derivatives

Publications (2)

Publication Number Publication Date
HK1136827A1 true HK1136827A1 (en) 2010-07-09
HK1136827B HK1136827B (en) 2012-09-28

Family

ID=

Also Published As

Publication number Publication date
KR20090114470A (en) 2009-11-03
EP2121691B1 (en) 2012-04-18
WO2008101660A1 (en) 2008-08-28
RU2009135070A (en) 2011-03-27
ES2386387T3 (en) 2012-08-20
CY1112725T1 (en) 2016-02-10
ECSP099621A (en) 2009-10-30
DK2121691T3 (en) 2012-07-02
EP2121691A1 (en) 2009-11-25
ATE554089T1 (en) 2012-05-15
AU2008217277A1 (en) 2008-08-28
PL2121691T3 (en) 2012-09-28
DE102007009319A1 (en) 2008-08-28
US20100048553A1 (en) 2010-02-25
CN101622256B (en) 2015-07-22
JP5514556B2 (en) 2014-06-04
SI2121691T1 (en) 2012-06-29
PT2121691E (en) 2012-05-25
HRP20120511T1 (en) 2012-07-31
RU2470933C2 (en) 2012-12-27
CO6220948A2 (en) 2010-11-19
CA2679173C (en) 2015-11-24
BRPI0806794A2 (en) 2011-09-13
IL200496A0 (en) 2010-04-29
KR101517748B1 (en) 2015-05-06
CN101622256A (en) 2010-01-06
NZ578589A (en) 2012-02-24
US7960404B2 (en) 2011-06-14
CA2679173A1 (en) 2008-08-28
ZA200906584B (en) 2010-06-30
JP2010519265A (en) 2010-06-03
AU2008217277B2 (en) 2012-09-06
MX2009007387A (en) 2009-07-17
IL200496A (en) 2014-02-27

Similar Documents

Publication Publication Date Title
RU2470933C2 (en) Spirocyclic cyclohexane derivatives
CA2550868C (en) Spirocyclic cyclohexane derivatives with affinity for the orl1-receptor
US7776848B2 (en) Spirocyclic cyclohexane compounds
US9120797B2 (en) Process for preparing spirocyclic cyclohexane compounds, compositions containing such compounds and method of using such compounds
TWI450899B (en) Substituted spirocyclic cyclohexane derivatives
US20090227571A1 (en) Androgen Receptor Modulator Compounds and Methods
US20050187281A1 (en) Spirocyclic cyclohexane derivatives
CA2679166A1 (en) Spirocyclic cyclohexane derivatives
US7232847B2 (en) 4-hydroxymethyl-1-aryl-cyclohexylamine compounds
US20050267107A1 (en) 4-alkyl-/4-alkenyl-/4-alkynyl methyl/-1-aryl-cyclohexylamine compounds
HK1136827B (en) Spirocyclic cyclohexane derivatives
TW201734009A (en) Substituted morpholine derivatives having activity against pain
HK1136828B (en) Spirocyclic cyclohexane derivatives
HK1129676B (en) Spirocyclic azaindole derivatives
HK1129676A1 (en) Spirocyclic azaindole derivatives
HK1095831B (en) Spirocyclic cyclohexane derivatives with affinity to the orl-1 receptor

Legal Events

Date Code Title Description
PC Patent ceased (i.e. patent has lapsed due to the failure to pay the renewal fee)

Effective date: 20190217